A woman with eptifibatide (integrilin)‐induced thrombocytopenia following treatment of a clot in her coronary artery: A case report and literature review

Abstract Eptifibatide, a GPIIb/IIIa receptor inhibitor, has shown its efficacy and safety in patients with high clot burden in their coronary vessels. It is widely used in patients with this condition. However, this medication use is accompanied by complications in some cases. Thrombocytopenia which is a relatively common condition in patients admitted to the hospital, especially in the acute setting, can be caused by medications. This condition can occur as an antibody or non‐antibody‐mediated process, caused by medications, such as heparin, clopidogrel, and eptifibatide. In this case, we present a woman with acute coronary syndrome and a complex lesion with a clot in her coronary vessel who was treated with eptifibatide. It led to asymptomatic thrombocytopenia. Once detected in laboratory data, the infusion was held, and the platelet count recovered in less than 5 days without additional treatment for this adverse effect. Eptifibatide is a medication used to treat acute coronary syndrome patients with a large thrombus in their coronary vessels. The mechanism of inducing thrombocytopenia by eptifibatide has not been proven yet, but it might be related to IgG antibodies. The severity of the disease can vary significantly, and the treatment is based on this factor. However, the main pillar of the treatment is the cessation of eptifibatide as soon as possible. This case draws the attention of physicians to one of the infrequent adverse effects of a commonly used medication in cardiology patients. Thrombocytopenia and its manifestations should be investigated and considered in patients who receive eptifibatide.

and eptifibatide.In this case, we present a woman with acute coronary syndrome and a complex lesion with a clot in her coronary vessel who was treated with eptifibatide.It led to asymptomatic thrombocytopenia.Once detected in laboratory data, the infusion was held, and the platelet count recovered in less than 5 days without additional treatment for this adverse effect.Eptifibatide is a medication used to treat acute coronary syndrome patients with a large thrombus in their coronary vessels.The mechanism of inducing thrombocytopenia by eptifibatide has not been proven yet, but it might be related to IgG antibodies.The severity of the disease can vary significantly, and the treatment is based on this factor.However, the main pillar of the treatment is the cessation of eptifibatide as soon as possible.This case draws the attention of physicians to one of the infrequent adverse effects of a commonly used medication in cardiology patients.
Thrombocytopenia and its manifestations should be investigated and considered in patients who receive eptifibatide.

K E Y W O R D S
acute coronary syndrome, adverse drug event, eptifibatide, thrombocytopenia, thrombosis 1 | INTRODUCTION Eptifibatide (integrilin) and Tirofiban are two medications used in patients with acute coronary syndrome to prevent platelet aggregation and clot formation.The mechanism of action is inhibition of the GPIIb/IIIa receptor and consequently, fibrinogen binding inhibition 1,2 The intravenous and intracoronary infusion of this group of medications has shown their efficacy in patients with a high burden of thrombus in their coronary vessels. 3Taking advantage of these medications was correlated with a significantly improved cardiovascular and overall outcome in patients with a high burden of thrombus. 3,4Sharma.et al. conducted a clinical trial and showed that intra-coronary administration of tirofiban was associated with improved clinical and angiographic outcomes in patients with high thrombus burden prior to their percutaneous coronary intervention (PCI). 42][3] Mostly, this adverse effect of this medication happens in the first 24 h after the initiation of the infusion of the medication. 5Eptifibatide thrombocytopenia can cause severe complications such as bleeding, paradoxical thrombosis, and prolonged hospital stays.Therefore, their use should be limited to selected cases with the necessary need for this medication, such as considerably diminished blood flow by a large thrombus. 5his study presents a case of a woman who presented to the emergency room with chest pain and received eptifibatide due to the observation of a large clot in her left circumflex artery (LCX).This woman had a declining platelet count trend with the start of the infusion and a reversal of the trend with the cessation of the medication.

| Case history and examination
The patient was a 58-year-old woman who presented with retrosternal pain that started 2 weeks before coming to the emergency department (ED).She described the pain as burning, intermittent (continued for 20 min), and improving following nitroglycerin use or resting.The pain occurred twice during the last 2 weeks before her presentation.The patient had gone to the emergency room 1 week before due to her previous chest pain episode.She was advised to be admitted to the hospital for more evaluation by a coronary angiography (CAG) by the medical team.However, she had declined the medical recommendation due to her occupational condition.She had no past medical history of ischemic heart disease but had hypertension and dyslipidemia from several years ago.In her past drug history, nitroglycerin, metoprolol, atorvastatin, and valsartan were mentioned.In her initial assessment, her vital signs were normal, and her physical examination was unremarkable.

| Methods
Following obtaining an electrocardiogram (ECG), which was immediately after taking the patient's history and performing a physical exam, ST-segment depression was detected in several precordial leads (Figure 1).At this presentation, all laboratory data, chest x-rays, and troponinlevel results were unremarkable.Considering her typical chest pain for ischemic heart disease and ECG evidence, she was admitted to the coronary care unit, and CAG was planned to be done urgently after her preparation.An urgent echocardiography while the catheter laboratory was being prepared demonstrated a left ventricular ejection fraction of 55%, and an abnormal septal motion.Then the patient was urgently transferred to the catheter laboratory.The CAG revealed that her right coronary artery had no significant lesion (Figure 2), her left anterior descending artery had an intimal irregularity in its proximal part, and her LCX had a complex lesion with a clot and was dominant (Figures 3 and 4).Due to clot observation, anticoagulation therapy was planned, and an integrin alpha IIbbeta3 antagonist eptifibatide drip infusion was initiated immediately.
The patient's condition remained stable, and no abnormal sign or symptom was seen until 3 h after the initiation of the medication.The patient stated feeling unusual fatigue.The cardiologist immediately evaluated the vital signs performed a complete physical exam and found no remarkable signs.Therefore, to make sure about the patient's appropriate clinical condition a series of laboratory data was requested.The complete blood counts 3 h after the initiation of the integrin alpha IIbbeta3 antagonist eptifibatide showed a decline of platelets from 206,000 cells/mm 3 to 80,0000 cells/mm 3 .Since the other medications that the patient was receiving were administered to her in her previous chest pain episode in the emergency room or were not known as a potential cause by eptifibatide.Moreover, a heparininduced thrombocytopenia test was done and was negative.Suspecting eptifibatide-induced thrombocytopenia, the drip infusion of the medication is stopped immediately.However, other treatments for acute coronary syndrome have been continued.Notably, it was concluded that the patient's fatigue was not due to her thrombocytopenia since her condition improved after a short time of resting and before the initiation of any change in her treatment.The patient's history was evaluated completely and no previous drug reaction or any exposure to this group of medication was found.The observed drug reaction was added to the patient's file as a note for her future visits or admissions.
F I G U R E 1 ST-segment depression was detected in several precordial leads of the patient's ECG.

F I G U R E 2
There was no significant lesion in the patient's right coronary artery.
F I G U R E 3 LCX was the dominant artery, there was a complex lesion with a clot in this artery.

| Conclusion and results
In the next complete blood count after cessation of infusion which was performed about 14 h after the change in the medication, the platelet count increased to 90,000, and then 101,000, 120,000, 143,000, 189,000, 205,000, and 212,000 cells/mm 3 in the following 5 days (Table 1).Clexane, which was the medication that the patient had received in her last emergency room admission due to chest pain showed no adverse effect was initiated instead of eptifibatide.One week after the admission, the CAG was repeated, and percutaneous catheter intervention was done on the LCX by stent implantation in this artery (Figures 5 and 6).The patient's condition improved, and she was discharged 1 day later without any complications.Treatment with aspirin, clopidogrel, metoprolol, atorvastatin, valsartan, and as-needed nitroglycerin was continued.In the 1-, 2-, and 8-week followup visits, the patient's symptoms were resolved, and her general condition improved significantly.No abnormal sign or symptom was detected in the patient's follow-up visits.Figure 7 provides both the first and the second CAG of the patient.
F I G U R E 4 LCX was the dominant artery and there was a complex lesion with a clot in this artery.

T A B L E 1
After holding the infusion of eptifibatide, the platelet count increased to 90,000 and gradually up to 205,000 cells/mm 3   Thrombocytopenia is defined as a platelet count of less than 150,000 cells/mm 3 .It is divided into three types: mild (100,000-149,000), moderate (50,000-99,000), and severe, which means less than 50,000 cells/mm 36 Thrombocytopenia is relatively common in hospitals, especially acute settings, with a prevalence ranging from 15% to 40%. 7The first step in approaching thrombocytopenia is repeating the complete blood count to make sure it is not a laboratory error, pseudo-thrombocytopenia, or thrombocytopenia due to hemodilution. 7Heparin is one of the medications that can cause thrombocytopenia by causing anti-body generation to form platelet factor 4 (PF4) and the heparin complex.Clopidogrel is another drug that can cause thrombocytopenia by inducing thrombotic thrombocytopenic purpura (TTP) or allergic reactions. 8,9The list of drug-induced thrombocytopenia is not limited to these medications.To differentiate the cause of thrombocytopenia these points should be considered that the thrombocytopenia caused by eptifibatide is steeper and occurs early (in hours) after initiation.However, heparin-induced thrombocytopenia is milder most of the time and it occurs in the fourth to twentieth day after initiation of medication. 10Moreover, another characteristic of eptifibatideinduced thrombocytopenia is its response to the cessation of medication.Similar to our patient, only cessation of this medication infusion would lead to recovery of the platelet count in most cases. 10ptifibatide is a medication used for patients with large thrombus in their coronary vessels, which has caused acute coronary syndrome.This drug inhibits GPIIb/IIIa and prevents platelet aggregation and clot formation with a mechanism separate from cyclooxygenase inhibitors and P2Y12 inhibitors.This would increase the rate of successful PCI and could cause better outcomes in patients undergoing this process.This medication is mainly used for non-ST-elevated acute coronary syndrome to improve interventional success. 11The platelet anti-aggregation effect of the bolus and drip infusion of eptifibatide can be observed as soon as 1 min and lasts for 4-6 h. 12 The mechanism of eptifibatide-induced thrombocytopenia is not well known, but it has been attributed to both antibody-mediated and non-antibody-mediated mechanisms. 13,14There are studies stating the probable mechanism of eptifibatide-induced thrombocytopenia.Bougie.et al. observed the tendency of attachment between the antibodies that recognize multiple target epitopes on the GPIIb/IIIa and the drug in a trial conducted on nine patients with tirofiban and eptifibatide-induced thrombocytopenia.They stated that this process can be seen as a natural process or as a cause of prior exposure to the medication. 13In another study, Gao et al. observed thrombocytopenia caused by IG-g-induced platelet aggregation in the presence of eptifibatide when they incubated normal human platelets with serum containing eptifibatidedependent antibodies.They concluded that this might be a mechanism of eptifibatide-induced thrombocytopenia. 15ost of the manifestations of this kind of thrombocytopenia are negligible, such as petechia or minor bleeding from intravenous access.However, more serious cases, such as gastrointestinal bleeding, hematuria, and life-threatening bleeding that need immediate management can be seen 16 The management of eptifibatide thrombocytopenia depends on the severity of the condition and the platelet count.Similar to other suspected drug-induced thrombocytopenia other causes should be investigated and ruled out by a complete history taking, physical examination, and laboratory data evaluation.Then the causing medication should be stopped as soon as possible and based on the severity of thrombocytopenia, observation, intravenous immunoglobulin (IVIG), high-dose corticosteroids, or even platelet transfusion in severe cases. 17Most of the patients are responsive to the cessation of medication, and the platelet count recovers mostly in 1-5 days.On the other hand, cases with a platelet count of less than 10,000 might need platelet infusion and cessation of other anti-platelet drugs.
F I G U R E 7 On the left: In the first percutaneous coronary intervention (PCI) there was no significant lesion in the patient's right coronary artery.On the right: Second percutaneous coronary angiography and stent implantation in the LCX artery.
T A B L E 2 A literature review of similar cases of eptifibatide-induced thrombocytopenia.

Treatment and the final consequence
Eptifibatide-induced severe thrombocytopenia after STelevation myocardial infarction (STEMI): A case report Zaid Gheith, et al. 16 69-year-old male ST-elevation myocardial infarction Gross hematuria and a petechial rash, platelet count of 3000cells/mm Although using IVIG as a treatment for this condition is not an option, corticosteroids might be used in refractory cases with severe and hard-to-stop bleeding. 18,19In Table 2, similar cases of eptifibatide-induced thrombocytopenia are mentioned.
In our case, fortunately, the patient had only laboratory manifestations (moderate thrombocytopenia), and there was no clinical presentation such as minor or major bleeding.Since the patient had received clexane before and showed no adverse effect to this medication, eptifibatide was replaced by this medication.The other positive aspect of this case was being responsive to the cessation of drip infusion and a recovering platelet count in less than 24 h without any additional treatment.

LEARNING POINT
In this case, we presented a woman without any history of thrombocytopenia or allergy to medications with a large clot in her LCX, which had been decided to be managed with eptifibatide.However, the moderately detected thrombocytopenia caused a change in the treatment strategy and the cessation of this medication.It can be concluded that in the use of eptifibatide, this adverse, although uncommon, should be considered by the physician, and if it occurs, should be approached by the cessation of medication and also treated based on the severity of thrombocytopenia and the clinical response of the patients.Moreover, during the transfusion, the platelet count should be monitored carefully, and regular evaluation for any abnormal signs and symptoms such as petechia, any minor or major bleeding, and epistaxis should be performed.Most cases are self-limited and will be managed by cessation of the medication.However, in severe cases, IVIG, high-dose corticosteroids, or even platelet transfusion might be indicated.

| STUDY LIMITATION
Since the echocardiography of the patient was not recorded as a video in the center, we could not access it and it was the limitation of our study.However, the written report of the echocardiography was documented and accessible, which is included in the case presentation.

F I G U R E 5 F I G U R E 6
Second percutaneous coronary angiography and stent implantation in the LCX artery.Second percutaneous coronary angiography, after stent implantation in the LCX artery.
in 5 days.

Title and Authors Age and sex Diagnosis (reason for receiving eptifibatide) Platelet count trend and symptoms Treatment and the final consequence
Morteza Safi: Conceptualization; data curation; formal analysis; project administration; supervision.Roozbeh Nazari: Conceptualization; data curation; resources; software; validation.Nahid Senobari: Investigation; Abbreviation: PCI, percutaneous coronary intervention.T A B L E 2 (Continued)